This dissertation presents novel sequential dose-finding designs that adjust for inter-individual pharmacokinetic variability in phase I cancer clinical trials. Unlike most traditional dose-finding designs whose primary goals are the determination of a maximum safe dose, the goal of our proposed designs is to estimate a patient-specific dosing function such that the responses of patients can achieve a target safety level. Extending from a single compartment model in the pharmacokinetic theory, we first postulate a linear model to describe the relationship between the area under concentration-time curve, dose and predicted clearance. We propose a repeated least squares procedure that aims to sequentially determine dose according to individual ability of metabolizing the drug. To guarantee consistent estimation of the individualized dosing function at the end of a trial, we apply repeated least squares subject to a consistency constraint based on an eigenvalue theory for stochastic linear regression. We empirically determine the convergence rate of the eigenvalue constraint using a real data set from an irinotecan study in colorectal carcinoma patients, and calibrate the procedure to minimize a loss function that accounts for the dosing costs of study subjects and future patients. When compared to the traditional body surface area and an equation based dosing methods, the simulation results demonstrate that the repeated least squares procedure control the dosing cost and allow for precise estimation of the dosing function. Furthermore, in order to enhance the generality and robustness of the dose-finding designs, we generalize the linear association to a nonlinear relationship between the response and a linear combination of dose and predicted clearance. We propose a two-stage sequential design, the semiparametric link-adapted recursion, which targets at individualizing dose assignments meanwhile adapting for an unknown nonlinear link function connecting the response and dose along with predicted clearance. The repeat least squares with eigenvalue constraint design is utilized as the first stage, and the second stage recursively applies an iterative semiparametric least squares approach to estimate the dosing function and determine dosage for next patient. The simulation results demonstrate that: at first, the performance of repeated least squares with eigenvalue constraint design is acceptably robust to model misspecifications; at second, as its performance is close to that of repeated least squares procedure under parametric models, the semiparametric link-adapted recursion does not sacrifice much estimation accuracy to gain robustness against model misspecifications; at last, compared to the repeated least squares procedure, the semiparametric link-adapted recursion can significantly improve the dosing costs and estimation precision under the semiparametric models.

Wang Xin Ning. / "May 2002." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 201-236). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Chen Yu. / Thesis submitted in: November 2001. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 98-112). / Abstracts in English and Chinese. / Acknowledgements --- p.I / List of publications --- p.II / Abstract --- p.III / Abstract (Chinese) --- p.IV / Abbreviations --- p.V / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Tea --- p.1 / Chapter 1.2 --- Green tea --- p.3 / Chapter a) --- Chemical composition of green tea --- p.3 / Chapter b) --- Pharmacological activities of green tea polyphenols --- p.6 / Chapter c) --- Pharmacokinetics of green tea polyphenols --- p.10 / Chapter 1.3 --- Objective --- p.14 / Chapter Chapter 2 --- Validation of analysis method for tea catechins --- p.15 / Chapter 2.1 --- Materials and methods --- p.16 / Chapter a) --- Preparation of a catechin-mixture from tea --- p.16 / Chapter b) --- Preparation of stock solutions --- p.18 / Chapter c) --- Preparation of biofluid samples --- p.18 / Chapter d) --- HPLC analysis of tea catechins --- p.19 / Chapter 2.2 --- Results --- p.21 / Chapter a) --- Catechin-mixture (tea extracts) --- p.21 / Chapter b) --- "Extraction from plasma, urine and feces" --- p.21 / Chapter c) --- HPLC analysis of biofluid samples --- p.23 / Chapter 2.4 --- Discussion --- p.26 / Chapter Chapter 3 --- Pharmacokinetics of tea catechins following administration of different doses of the catechin-mixture --- p.32 / Chapter 3.1 --- Materials and methods --- p.33 / Chapter a) --- Surgery and animal maintenance --- p.33 / Chapter b) --- Dosing and sample collection --- p.33 / Chapter c) --- Pharmacokinetics analysis of tea catechins --- p.35 / Chapter 3.2 --- Results --- p.36 / Chapter 3.3 --- Discussion --- p.50 / Chapter Chapter 4 --- Pharmacokinetics of tea catechins following administration of different doses of individual catechins --- p.52 / Chapter 4.1 --- Materials and methods --- p.53 / Chapter a) --- Chemicals and reagents --- p.53 / Chapter b) --- Pharmacokinetic study of tea catechins and the HPLC analysis --- p.53 / Chapter c) --- Pharmacokinetic analysis of tea catechins --- p.54 / Chapter 4.2 --- Results --- p.55 / Chapter 4.3 --- Discussion --- p.67 / Chapter Chapter 5 --- Plasma protein binding of tea catechins --- p.69 / Chapter 5.1 --- Introduction --- p.69 / Chapter 5.2 --- Materials and methods --- p.72 / Chapter a) --- Ultrafiltration --- p.72 / Chapter b) --- Preparation of stock solution --- p.73 / Chapter c) --- Determination of nonspecific binding of the catechins --- p.73 / Chapter d) --- Determination of ultrafiltration conditions --- p.74 / Chapter e) --- In vitro plasma protein binding assay --- p.74 / Chapter f) --- Statistical analysis --- p.75 / Chapter 5.3 --- Results --- p.76 / Chapter a) --- Nonspecific binding in ultrafiltration --- p.76 / Chapter b) --- Protein binding of the catechins --- p.76 / Chapter c) --- Statistical analysis --- p.76 / Chapter 5.4 --- Discussion --- p.80 / Chapter Chapter 6 --- Partition of tea catechins in red blood cell --- p.82 / Chapter 6.1 --- Materials and methods --- p.83 / Chapter a) --- Prepare of stock solution --- p.83 / Chapter b) --- In-vitro erythrocyte partition --- p.83 / Chapter c) --- Data Analysis --- p.83 / Chapter 6.2 --- Results --- p.85 / Chapter a) --- Selection of experiment conditions --- p.85 / Chapter b) --- Partition of catechins to RBC --- p.85 / Chapter 6.3 --- Discussion --- p.87 / Chapter Chapter 7 --- Comparison of pharmacokinetics of tea catechins in mixture form versus pure compound --- p.89 / Chapter Chapter 8 --- Conclusion --- p.95 / References --- p.98

Avaliaram-se as alterações na eliminação da antipirina e de seus principais produtos de biotransformação, 3-hidroximetilantipirina (3HMA), 4-hidroxiantipirina (4HOA) e norantipirina (NORA) em pacientes portadores de doenças hepáticas. Investigaram-se onze pacientes com cirrose hepática confirmada por biopsia, nove pacientes com esquistossomose hepatesplênica e vinte e cinco voluntários sadios. Os \"clearancesn total e hepático da antipirina foram reduzidos com prolongamento de sua meiavida de eliminação nos pacientes cirróticos. Os \"clearances\" de formação da 3HMA, 4HOA e NORA também foram reduzidos como consequência de seu comprometimento hepático. Os pacientes com esquistossomose hepatesplênica mostraram alterações no metabolismo da antipirina, afetando os \"clearances\" de formação da 3HMA e da 4HOA, enquanto que para a NORA este parãmetro manteve-se inalterado. Deste modo, a determinação do \"clearance\" total da antipirina e da excreção urinária da antipirina e seus principais produtos de biotransformação mostrou ser teste útil para avaliar o metabolismo oxidativo nas doenças hepáticas. / Changes on elimination of antipyrine and its main metabolites, 3-hydroxymethylantipyrine (3HMA), 4hydroxyantipyrine (4HOA) and norantipyrine (NORA) in patients with liver disease were evaluated. Eleven patients with liver cirrhosis virus B, biopsy confirmed, nine patients with hepatesplenic shistosomiasis and twenty-five healthy volunteers were investigated. Total body clearance and hepatic clearance of antipyrine were reduced with prolongation of its elimination half-life in cirrhotic patients. Clearances for production of 3HMA, 4HOA and NORA were reduced as a consequence of this liver impairment. Patients with hepatesplenic shistosomiasis showed changes on antipyrine metabolism affecting only the clearance for production of 3HMA and 4HOA, while NORA was unchanged. Therefore, the determination of antipyrine plasma clearance and urinary excretion of antipyrine and its main metabolites showed to be a usefu

Doctor Pharmaceuticae - DPharm / Introduction: Drug-resistant tuberculosis remains a major world health problem and one of the leading cause of death worldwide. Despite adequate adherence to antituberculosis drugs by patients, the emergence of drug-resistance tuberculosis still occurs. This fact implies other factors leading to the emergence of resistant strains of Mycobacterium tuberculosis. A multidrug treatment regimen, which may consist of five to seven different drugs including terizidone, is used in the treatment of drugresistance tuberculosis. Terizidone is part of the multidrug regimen whose pharmacokinetics is scarce in literature and plasma concentration profile unknown. Two molecules of cycloserine joined by terephtalaldehyde moiety makes up a molecule of terizidone, which is thought to undergo complete metabolism into cycloserine in vivo. Additionally, the current literature report that terizidone and cycloserine can be used interchangeably as they are thought to be equivalent. The aim of this thesis was first to develop and validate bioanalytical methods for determination of terizidone and cycloserine in patients’ plasma samples. Secondly, to model population pharmacokinetics of terizidone and cycloserine. Thirdly, to determine the amount of cycloserine resulting from metabolism of terizidone.

Artemisinin compounds are the most potent anti-malarial drugs available in the market. Today, malaria treatment is largely relies on the artemisinin-based combination therapies. Artesunate (AS) is the most widely used artemisinin derivative. In this thesis, we characterized the population pharmacokinetics of AS and its active metabolite dihydroartemisinin (DHA) following oral administration of AS in different populations. In Chapter II, we developed a population pharmacokinetic model of AS and DHA in healthy subjects. These subjects received either single- or multiple-dosing of oral AS, as a monotherapy regimen or in combination with pyronaridine, with or without food. In Chapter III, we developed a population pharmacokinetic model of AS and DHA in adult and pediatric patients with uncomplicated falciparum and vivax malaria who were administered oral pyronaridine/artesunate combination once daily for 3 days. We modeled the AS and DHA data simultaneously using a parent-metabolite model that assumed complete conversion of AS to DHA. Following oral administration, AS is rapidly absorbed with maximum concentrations reached at about 0.5 hours post-dose. AS is rapidly converted to DHA. DHA then undergoes rapid metabolism, with an elimination half-life of about 0.8 hours in malarial patients. Inter-individual variability for almost all pharmacokinetic parameters and residual variability for both compounds were estimated by the models. Substantial variability was seen in the pharmacokinetic parameters between the subjects. In healthy subjects, intake of food with the dose was found to delay the absorption of AS significantly, but not the extent of absorption. Weight was also included in this model as a determinant of DHA clearance. When modeling the data from patients, we included weight as part of the model a prioria priori using an established allometric function. No other covariates examined in the analysis were statistically significant. The performance of final models was evaluated using non-parametric bootstrap technique and visual predictive check. The models were found to adequately described the data at hand, and robust with sufficient predictive power. The results can be used as the base to develop a population pharmacokinetic-pharmacodynamic model and as prior information in guiding the selection of optimal sampling schedule for future pharmacokinetic studies of AS.

Purpose: Ivermectin (IVM) is a lipophilic BCS-II compound (molecular weight=875 g/mole, LogP=3.22, intrinsic solubility=700 ug/L). IVM is used as antiparasitic drug in both humans and animals. IVM is known to have a half-life of 12-56 hours in humans. Strongyloidiasis is a chronic parasitic infection of humans caused by Strongyloides stercoralis, with an estimated 30-100 million people infected worldwide. Infection may be severe and even life-threatening in cases of immunodeficiency. Patients with disseminated strongyloidiasis are usually bedridden hospitalized patients that show symptoms such as paralytic ileus and reduced plasma albumin and cholesterol. Oral IVM is the only FDA-approved treatment but may not be effective in patients with disseminated disease. Veterinary subcutaneous formulations have been used in severe infections. We hypothesized that IVM PK in patients with disseminated strongyloidiasis can be predicted using PBPK model originally built and refined in healthy human and animal species. This hypothesis was tested and shown to be valid. Methods:A systematic method was used to build and refine different parts of the PBPK model. The process involved construction of models, parameterization of these models, evaluation of the effect of uncertainty in model parameters on model prediction via local and global sensitivity analyses and finally, refinement of model predictions. Two disposition models that differ in the rate limiting step in drug distribution were constructed and include perfusion-limited and permeability-limited distribution models. The ability of each model to predict IVM disposition was evaluated using plasma PK data in rat after intra-arterial dosing and in dog after intravenous bolus dosing. Then the disposition model was scaled to humans and an oral input model was constructed as a modification on the well-known ACAT model. The oral input model was coupled with the disposition model and used to predict IVM plasma concentration-time profile in healthy fasted human subject after oral dosing. Two subcutaneous (SQ) input models were constructed and used to evaluate the effect of IVM precipitation at the injection site. Plasma PK data in dog after SQ dosing was used to refine the constructed SQ input models. The refined disposition, oral input and SQ input physiologically-based models were used to predict IVM PK in patients with disseminated strongyloidiasis after a complex dosing regimen. The physiological parameters of the model were modified to account for the effect of the disease-induced pathophysiological changes on the body physiology and hence on the drug PK. Plasma PK data from hospitalized subjects with disseminated strongylidiasis was used in this part. Results and conclusions:The disposition model with assumption of permeability-limited distribution was more capable of describing IVM disposition in rat after intra-arterial dosing compared to when perfusion-limited distribution was assumed. The model predicted that hepatic clearance is the most impactful parameter on model-predicted plasma concentration of the drug. Also, IVM was shown to have low hepatic extraction ratio along with high binding in plasma and large volume of distribution, which collectively may explain the long half-life in the plasma of 63 hours in rat after intra-arterial dosing. The oral input model predicted that the oral input is limited by drug dissolution in the GI lumen and that a very small fraction of oral tablet dose (0.03) is available in the systemic circulation in healthy fasted human subjects. Both of the studied SQ input models predicted that majority of IVM absorption after SQ dosing is via the lymphatic route and that drug precipitation at the injection site can further slowdown the drug absorption after SQ administration. The PBPK model was able achieve the main goal of this research which is to predict IVM pharmacokinetics in patients with disseminated strongyloidiasis after a complex dosing regimen of multiple oral and SQ dosing. This was achieved by modifying the most impactful physiological parameters of the model affected by the disease state and that are related to drug binding in the plasma (fraction unbound), the GI motility (gastric emptying rate) and the lymphatic flow rate. Based on our analysis, we recommend measurement of plasma IVM concentrations early after initiation of therapy to exclude treatment failure due to reduced oral and/or SQ absorption. Also, we recommend measurement of plasma lipoprotein levels and their composition in these patients to differentiate between low total plasma concentrations due to low binding plasma as opposed to low drug input. Finally, interventional procedures that enhance lymphatic flow rate to site of SQ injection are recommended to enhance SQ absorption.

Artemisinin derivatives are key to the current global treatment approach for malaria. However, much remains unknown regarding the pharmacokinetics of these agents, particularly in children and pregnant women, two groups highly vulnerable to development of severe malaria infection. In this thesis, nonlinear mixed effects modeling is used to characterize the pharmacokinetics of the artemisinin derivative artesunate and its active metabolite, dihydoartemisinin (DHA), in children and in pregnant women. Chapter 1 of this thesis contains a general review of the clinical pharmacokinetic findings for artesunate and DHA following artesunate administration by the intravenous, intramuscular, oral and rectal routes. Chapter 2 presents a population pharmacokinetic model utilizing both pediatric and adult data from one Phase II and four Phase III clinical trials evaluating the combination agent pyronaridine tetraphosphate/artesunate. The focus of the modeling described in this chapter is the evaluation of the effects of body size and gender on the pharmacokinetics of artesunate and DHA in pediatric patients with uncomplicated malaria. Chapter 3 consists of a population pharmacokinetic model built utilizing plasma artesunate and DHA concentrations from 26 parasitemic second and third trimester pregnant women and 25 parasitemic non-pregnant female controls in the Democratic Republic of Congo who received 200 mg oral artesunate. The model described in Chapter 2 is a simultaneously implemented parent-metabolite model consisting of a one compartment model for artesunate, a one compartment model for DHA, and first-order artesunate absorption. Various approaches for incorporating body size on artesunate and DHA apparent clearance and volume of distribution parameters were evaluated, with a linear body surface area model and an allometric scaling model both proving satisfactory. The effect of gender was modeled on artesunate and DHA apparent clearance and volume terms. Only the effect of gender on DHA apparent clearance could be estimated with reasonable precision, with the 95% confidence interval for the effect being almost wholly contained within the predefined 0.75 to 1.25 no relevant clinical effect interval. The model described in Chapter 3 consists of a one compartment model for artesunate, a one compartment model for DHA, and mixed zero-order, lagged first order absorption of artesunate. In this model, pregnancy was found to have a marked effect on DHA apparent clearance, with a pregnancy-associated increase in DHA apparent clearance of 42.3%. The models described in this thesis indicate that, for a given mg/kg dose of artesunate, both young children and pregnant women would be expected, on average, to display lower DHA concentrations than would be observed following administration of the same mg/kg dose to non-pregnant adults. Suboptimal dosing has clinical implications for the individual as well as potential implications regarding parasite susceptibility. Given this, the findings of the research described in this thesis highlight the necessity of investigations designed to comprehensively characterize the pharmacokinetics of artesunate and DHA in these two highly susceptible populations.

In this thesis, the population pharmacokinetics of telapristone and its active metabolite, CDB-4453 was evaluated using nonlinear mixed effects modeling (NONMEM®). A two-compartment (parent) one compartment (metabolite) mixture model with first order absorption and elimination adequately described the pharmacokinetics of telapristone and CDB-4453. For the Phase I/II pharmacokinetic analysis (effect of renal and hepatic impairment), telapristone was rapidly absorbed with an absorption rate constant (Ka) of 1.26 h-1. Moderate renal impairment resulted in a 74% decrease in Ka. Population estimates for oral clearance (CL/F) for the high and low clearance groups were 11.6 L/h and 3.34 L/h, respectively. Twenty-five percent of the subjects were allocated to the high clearance group. Apparent volume of distribution for the central compartment (V2/F) was 37.4 L, apparent inter-compartmental clearance (Q/F) was 21.9 L/h, and apparent peripheral volume of distribution for the parent (V4/F) was 120 L. The ratio of the fraction of telapristone converted to CDB-4453 to the distribution volume of CDB-4453 (Fmetest) was 0.20/L and apparent clearance of the metabolite (CLM/F) was 2.43 L/h. For the pharmacokinetic analysis evaluating the effect of food; food decreased the Ka of telapristone (Ka for the fed and fasted state was 0.467 and 5.06 h-1, respectively). Population estimates of the high and low CL/F groups were 12.0 L/h and 3.15 L/h, respectively. Thirty-one percent of the subjects were allocated to the high clearance group. V2/F, Q/F and V/4 and Fmetest were 52.8 L, 7.53 L/h, 84.8 L and 0.193/L, respectively. CLM/F was 2.10 L/h. An external validation was performed using the final parameter estimates from the pooled pharmacokinetic analysis (effect of renal and hepatic impairment and the effect of food). From this pharmacokinetic analysis, Ka for the fed and fasted state was 0.299 and 2.35 h-1, respectively. Population estimates for the high and low CL/F groups were 11.6 L/h and 3.22 L/h, respectively. The percentage of subjects allocated to the high clearance group was 29%. V2/F, Q/F, V/4 and Fmetest were 52.8 L, 11.6 L/h and 93.8 L and 0.186/L, respectively. CLM/F was 2.23 L/h. The final model did not meet the requirement for adequate predictability using the external validation dataset. However, the external validation dataset only included samples with limited early time points. Because of the limited sampling times, it is difficult to make a conclusion about the overall adequacy of the model. An external validation dataset with more extensive sampling will be needed in order to better assess the predictability final model. This is the first comprehensive review of the pharmacokinetics of telapristone and CDB-4453.

This dissertation describes how to apply pharmacokinetic simulations and modeling in a clinical setting to monitor and adjust drug dosing in special patient populations. Pharmacokinetic simulations were used to investigate efficacy and risk of drug toxicity of a new dosing regimen for aminoglycoside antibiotics when administered to renal failure patients. The current method of administering aminoglycosides to renal failure patients is to dose the drug during the last half hour of dialysis sessions. The new proposed method suggests dosing the drug during the first half hour of the dialysis session. Using one-compartment model infusion equations, both methods were simulated to predict drug peaks, troughs and area under the curves. These parameters were used to compare both dosing regimens to find out if the proposed dosing regimen can be suggested in a clinical setting to obtain the same efficacy and lower risk of drug toxicity. The dissertation then describes a prospective clinical study in chronic renal failure patients who received the same tobramycin dose using current and proposed dosing regimens. Results from the clinical study confirm pharmacokinetic simulations and modeling outcomes. Results suggest that both regimens have the same efficacy, but the new proposed method is expected to have lower risk of drug toxicity. The dissertation also describes a retrospective study for vancomycin dosing in renal failure patients. The objective was to confirm that pharmacokinetic modeling could be used to predict and adjust vancomycin dosing for this special population. Vancomycin trough concentrations obtained from patient medical records were compared to predictions obtained using a pharmacokinetic model. It was concluded that there was no statistically significant difference between actual and predicted vancomycin trough concentrations. These results suggest that the pharmacokinetic model can be used to predict and adjust vancomycin dosing to chronic renal failure population. The last part of this dissertation describes evaluation of insulin glargine effect on glycemic control and weight change in a diabetic population. Glycemic control and weight of patients before and after initiation of insulin glargine were evaluated retrospectively. Results showed that initiation of insulin glargine improved glycemic control while weight remained relatively stable. / Graduation date: 2005